Two manifolds for metal-catalyzed intramolecular Diels-Alder reactions of unactivated alkynes

Article abstract of DOI:10.1002/anie.200703321

Being unconventional: Although conventional metal-catalyzed [4+2] cycloaddicloadditions of inactivated dienynes are known to proceed by an oxidative cyclization/insertion mechanism, two entirely different pathways also result in formal Diels-Alder reactio

Full text of DOI:10.1002/anie.200703321

Angewandte
Chemie
DOI: 10.1002/anie.200703321
Cycloadditions
Two Manifolds for Metal-Catalyzed Intramolecular Diels–Alder
Reactions of Unactivated Alkynes**
Alois Fürstner* and Christopher C. Stimson
The poor reactivity of unactivated alkynes as dienophiles has
for a long time limited their use in Diels–Alder reactions.[1]
Only after the discovery of the remarkable catalytic effect of
various transition-metal complexes could the synthetic poten-
tial of this transformation be exploited.[2–4] Such cycloaddi-
tions of dienynes A are assumed to proceed via metallacyclic
intermediates of type B and C, which are formed by oxidative
cyclization, and subsequent insertion of the alkyne
(Scheme 1).[3] We speculated, however, that entirely different
scenarios might also result in a net [4+2] cycloaddition, and
present herein preliminary data to support this view.
in situ (Table 1). Whereas the parent compounds 1 decom-
posed (Table 1, entry 1), substrates with a nonterminal alkyne
were converted into the corresponding 1,4-cyclohexadiene
Table 1: Gold-catalyzed cycloadditions;[a] E=COOEt.
Entry
Substrate
Product
Yield
1
–
[b] (X=CE2, NTs, O)
2
3
4
75% (X=CE2)
91% (X=NTs)
40% (X=C(SO2Ph)2)
5
6
82%[c]
81%[c]
Scheme 1. Different scenarios for metal-catalyzed Diel-Alder reactions
of dienynes. Top: conventional pathway based on oxidative cyclization;
bottom: novel electrophilic activation manifold.
7
8
70% (R=SnBu3)
63% (R=CH2OAc)
[a] [(Ph3P)AuCl] (5 mol%), AgSbF6 (5 mol%), CH2Cl2, RT. [b] Decom-
position. [c] The product is partly aromatized in air (ca. 10%). Ts=
toluene-4-sulfonyl.
Activation of the triple bond of A followed by attack of
the dieneꢀs proximal alkene moiety should generate an
electrophilic metal carbene F with a pendant vinyl group on
its cyclopropyl ring.[5] This species might undergo a “metalla-
Cope” rearrangement with formation of C and proceed from
there on; alternatively, one may envisage formation of cation
G that releases cycloadduct D and regenerates the catalyst.
The excellent performance of cationic gold complexes as
carbophilic Lewis acids[5] prompted us to probe this concept
by exposing various dienynes to [(Ph3P)Au]SbF6 generated
products in respectable yields. As silyl end groups on the
alkyne are lost upon work-up,[6] access to the unfunctionalized
cycloadducts is secured (Table 1, entries 2–6).
The proposed mechanism, which proceeds via an inter-
mediate of type F, is consistent with the results shown in
Scheme 2. Thus, compound 10 furnished cycloadduct 12
(68%) and tetrahydrofuran 13 (15%), which derives from
the putative electrophilic carbene 11 by reaction with the
tethered alcohol; such vinylogous alkoxycyclizations have
ample precedence in gold and platinum catalysis.[7] Even
more instructive is the conversion of substrate 14 into 16 and
18, both of which again likely originate from the same
intermediate 15. Whereas evolution of this species along the
pathway depicted in Scheme 1 affords cycloadduct 16, com-
peting attack of the phenyl ring onto the electrophilic carbene
provides the companion product 18. The latter course
corroborates the view that gold cyclopropyl “carbenes”
[*] Prof. A. Fürstner, Dr. C. C. Stimson
Max-Planck-Institut für Kohlenforschung
45470 Mülheim an der Ruhr (Germany)
Fax: (+49)208-306-2994
E-mail: fuerstner@mpi-muelheim.mpg.de
[**] Generous financial support from the MPG and the Fonds der
Chemischen Industrie is gratefully acknowledged. We thank Dr. R.
Mynott and his team for expert NMR spectroscopic support and Dr.
C. W. Lehmann for solving the X-ray structure.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 8845 –8849
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
cycloadduct 2a in high yield (Table 2). It is noteworthy that
even one equivalent of CuI in the absence of the base did not
lead to any significant rate acceleration over the thermal
Table 2: Optimization of the copper-catalyzed Diels–Alder reaction.
Entry
CuX
Base
Et3N
T [8C]
t [h]
Yield [%]
1
2
3
4
5
6
–
70
70
20
20
20
20
18
18
18
6
6
6
25
30
trace
75
92
CuI (100%)
CuSO4 (10%)
CuCl (10%)
CuI (10%)
CuTC (10%)[b]
–
[a]
Et3N
Et3N
–
95
[a] Sodium ascorbate. [b] CuTC=copper thiophene-2-carboxylate.
background reaction (Table 2, compare entries 1 and 2). This
observation suggests that a copper acetylide must be gen-
erated for the cycloaddition to proceed. In line with this,
copper thiophene-2-carboxylate[11] was found to be an active
catalyst since this particular salt can simultaneously act as a
CuI source and as a base (Table 2, entry 6).
Scheme 2. a) [(Ph3P)AuCl] (5 mol%), AgSbF6 (5 mol%), CH2Cl2, 12
(68%), 13 (15%); b) [(Ph3P)AuCl] (5 mol%), AgSbF6 (5 mol%),
CH2Cl2, 78% (16/18 ca. 3:4).
The intervention of a copper acetylide M is also consistent
with the observation that only terminal alkynes participate in
such cycloadditions, whereas end-capped substrates are
recovered unchanged (Table 3, entries 4 and 5). This inherent
limitation notwithstanding, the scope of the reaction is broad:
it encompasses different tethers and tolerates various func-
tional groups including free hydroxy groups, silyl ethers,
esters, sulfonamides, sulfones, and even alkyl halides
(Table 3). Moreover, substrates with 1,4-disubstituted dienes
give the corresponding cis-configured bicycles with excellent
selectivity (Table 3, entries 7–9, see below).
The same reaction conditions also allowed a series of
formal hetero-Diels–Alder reactions[12] to be performed
under equally mild conditions (Table 3, entries 10–15).[13]
Therefore, this novel protocol constitutes an alternative to
the ruthenium-based methodology previously used to prepare
annelated [3,4-c]pyrans of this type.[14] The mildness of the
new method greatly contributes to the success, because such
cyclic bis-enol ethers are highly sensitive and must be handled
with great care under acid-free, non-oxidative conditions.
Although these results seem to imply copper acetylides as
reactive intermediates, further evidence for the proposed
mechanism was sought. To this end, substrate 1a was treated
with CuI/Et3N (1 equiv) in rigorously dried MeOD
(Scheme 4). The fact that the resulting product had incorpo-
rated a deuterium label ([D]-2a) is consistent with a vinyl-
copper species 30 intervening. However, non-negligible
amounts of H-2a were also produced ([D]-2a/H-2a ca. 4:1),
despite considerable efforts to exclude all traces of adventi-
tious water. This result indicates that the generated ammo-
nium salt Et3N·HI reenters the scene and likely plays a pivotal
role in closing the catalytic cycle if the reaction is performed
resemble “nonclassical cations” in behavior.[5,8] Since similar
compounds have previously been observed in enyne cyclo-
isomerizations known to proceed via metal cyclopropyl
carbenoids,[9] the isolation of 18 provides strong evidence
for the proposed “electrophilic” pathway.
We envisaged that yet another, entirely different, scenario
might also allow unactivated alkynes to take part in Diels–
Alder reactions. In analogy to the copper-catalyzed ligation of
azides and terminal alkynes, which is thought to proceed from
acetylide I, via the cyclic vinylidene J, to the vinylcopper
species K,[10] a similar pathway for dienynes can be conceived
(Scheme 3). In fact, compound 1a reacts with catalytic
amounts of CuX in the presence of Et3N in CH2Cl2 to give
Scheme 3. Tentative mechanism of copper-catalyzed azide cycloaddi-
tions[10] and the envisaged Diels–Alder manifold involving analogous
copper acetylide (-vinylidene) and -vinyl intermediates.
8846 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8845 –8849
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Angewandte
Chemie
Table 3: Copper-catalyzed Diels–Alder and hetero-Diels–Alder reactions
of unactivated dienynes;[a] E=COOEt.
Entry
Substrate
Product
Yield[b]
1
2
3
92% (X=CE2)
95% (X=NTs)
76% (X=C(SO2Ph)2)
4
5
0% (R=Me)
0% (R=SiMe3)
Scheme 5. Proposed catalytic cycle upon the use of mesitylcopper
(31).
6
80%
7
8
9
95% (X=OH)
69% (X=OTBS)
92% (X=I)
cycloaddition to be performed at ꢀ788C. Since catalytic
amounts of 31 suffice to reach complete conversion, a proton
transfer from the substrateꢀs terminal alkyne to the putative
vinylcopper intermediate must occur, which allows the overall
reaction to be separated into an “initiation” and a “prop-
agation” phase.
This analysis suggests that it might be possible to outper-
form this rapid proton transfer with other electrophiles. In
fact, a series of intramolecular trapping experiments gave
excellent results and led to tricyclic products by an unprece-
dented copper-mediated [4+2] cycloaddition/alkylation cas-
cade (Scheme 6). Primary iodides, an aldehyde, as well as an
enoate were found to be suitable as electrophilic partners.[16]
The products were obtained with excellent levels of stereo-
selectivity, with the lateral rings being invariably fused in a
1,4-cis manner to the core, as evident from pertinent NMR
10
11
12
83% (R=H)
70% (R=Me)
67% (R=Ph)
13
100%[c]
14
15
100% (R=H)[c]
100% (R=Ph)[c]
[a] All reactions were performed withCuI (10 mol%) and Et 3N (1 equiv)
in CH2Cl2 at RT. [b] Yields of isolated product. [c] GC yield, see text for
more details. TBS=tert-butyldimethylsilyl.
Scheme 4. Deuteration experiment which indicates that a vinylcopper
intermediate may react withdifferent proton sources to close the
catalytic cycle; 90% ([D]-2a/H-2a ca. 4:1).
in aprotic media. Alternatively, one may envisage that the
substrate itself serves as a proton source, as its terminal
alkyne should be acidic enough to react with 30, release the
product, and thereby regenerate the catalytically competent
intermediate 29. To probe this possibility, 1a was treated with
mesitylcopper (31)—one of the few thermally robust organo-
copper species that can be readily isolated in pure form
(Scheme 5).[15] In this case, formation of the copper acetylide
generates mesitylene which cannot react with any organo-
copper intermediate later in the catalytic cycle. In fact, 31
turned out to be exceptionally active, thus allowing the
Scheme 6. Copper-mediated Diels–Alder/alkylation cascade; a) mesi-
tylcopper (31, 1 equiv), THF, ꢀ788C!RT.
Angew. Chem. Int. Ed. 2007, 46, 8845 –8849
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
1H), 2.53 (dd, J = 11.2, 9.0 Hz, 1H), 2.40 (s, 3H), 2.17 (dddd, J = 16.6,
10.0, 2.6, 2.4 Hz), 2.08 (dddm, J = 16.4, 9.2, 8.8 Hz, 1H), 2.01 (dtm, J =
11.8, 6.9 Hz, 1H), 1.76 (ddddd, J = 12.7, 8.8, 7.1, 2.8, 1.5 Hz, 1H), 1.64
(ddddd, J = 12.9, 11.7, 10.0, 9.2, 6.6 Hz, 1H), 1.03 ppm (dq, J = 12.0,
7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 143.4, 135.3, 133.9,
130.5, 129.7, 127.4, 124.7, 124.1, 52.6, 49.0, 42.0, 39.6, 32.2, 27.4, 24.0,
21.5 ppm; for the full data set, see the Supporting Information.
data and from the structure of 35 in the solid sate
(Figure 1).[17–19] These trapping experiments provide compel-
ling evidence for the intervention of a vinylcopper species of
Received: July 24, 2007
Published online: October 17, 2007
Keywords: alkynes · copper · cycloaddition · gold ·
.
tandem reactions
[1] a) W. Carruthers, Cycloaddition Reactions in Organic Synthesis,
Pergamon, Oxford, 1990; b) W. R. Roush, in Comprehensive
Organic Synthesis, Vol. 5 (Eds.: B. M. Trost, I. Fleming),
Pergamon, Oxford, 1991, pp. 513 – 550; c) K. C. Nicolaou, S. A.
Snyder, T. Montagnon, G. Vassilikogiannakis, Angew. Chem.
2002, 114, 1742 – 1773; Angew. Chem. Int. Ed. 2002, 41, 1668 –
1698; d) E. J. Corey, Angew. Chem. 2002, 114, 1724 – 1741;
Angew. Chem. Int. Ed. 2002, 41, 1650 – 1667; e) A. G. Fallis, Acc.
Chem. Res. 1999, 32, 464 – 474; f) K. Takao, R. Munakata, K.
Tadano, Chem. Rev. 2005, 105, 4779 – 4807.
Figure 1. One of the two independent molecules of 35 in the solid
state. Anisotropic displacement parameters are drawn at the 50%
probability level.
type O (Scheme 3), and hence exclude metallacycles of type B
that are usually invoked in [4+2] cycloadditions catalyzed by
low-valent-metal complexes.[3] Although we concede that the
mechanism of this novel copper-catalyzed Diels–Alder pro-
tocol deserves further study in the laboratory and in silico, in
particular to clarify if the conversion of M into O proceeds
directly or involves vinylidenes of type N or N’, all the
available data imply that a reaction mechanism beyond that
of conventional schemes is operative.
[2] For pioneering studies, see a) A. Carbonaro, A. Greco, G.
DallꢀAsta, J. Org. Chem. 1968, 33, 3948 – 3950; b) J. P. GenÞt, J.
Ficini, Tetrahedron Lett. 1979, 20, 1499 – 1502; c) H. tom Dieck,
R. Diercks, Angew. Chem. 1983, 95, 801 – 802; Angew. Chem. Int.
Ed. Engl. 1983, 22, 778 – 779; d) P. A. Wender, T. E. Jenkins, J.
Am. Chem. Soc. 1989, 111, 6432 – 6434; e) I. Matsuda, M.
Shibata, S. Sato, Y. Izumi, Tetrahedron Lett. 1987, 28, 3361 –
3362; f) R. S. Jolly, G. Luedtke, D. Sheehan, T. Livinghouse, J.
Am. Chem. Soc. 1990, 112, 4965 – 4966.
[3] a) P. A. Wender, J. A. Love, Adv. Cycloaddition, Vol. 5 (Ed.: M.
Harmata), JAI Press, Greenwich, 1999, pp. 1 – 45; b) M. Lautens,
W. Klute, W. Tam, Chem. Rev. 1996, 96, 49 – 92; c) C. Aubert, O.
Buisine, M. Malacria, Chem. Rev. 2002, 102, 813 – 834.
Experimental Section
[4] For leading references, see a) P. A. Wender, T. E. Smith,
Tetrahedron 1998, 54, 1255 – 1275; b) P. A. Wender, T. E. Jenkins,
S. Suzuki, J. Am. Chem. Soc. 1995, 117, 1843 – 1844; c) S. R.
Gilbertson, G. S. Hoge, D. G. Genov, J. Org. Chem. 1998, 63,
10077 – 10080; d) M. Murakami, M. Ubukata, K. Itami, Y. Ito,
Angew. Chem. 1998, 110, 2362 – 2364; Angew. Chem. Int. Ed.
1998, 37, 2248 – 2250; e) D. J. R. OꢀMahony, D. B. Belanger, T.
Livinghouse, Org. Biomol. Chem. 2003, 1, 2038 – 2040; f) B.
Witulski, J. Lumtscher, U. Bergsträßer, Synlett 2003, 708 – 710;
g) D. Motoda, H. Kinoshita, H. Shinokubo, K. Oshima, Angew.
Chem. 2004, 116, 1896 – 1898; Angew. Chem. Int. Ed. 2004, 43,
1860 – 1862; h) A. Saito, T. Ono, A. Takahashi, T. Taguchi, Y.
Hanzawa, Tetrahedron Lett. 2006, 47, 891 – 895; i) G. Hilt, W.
Hess, K. Harms, Org. Lett. 2006, 8, 3287 – 3290; j) B. Wang, P.
Cao, X. Zhang, Tetrahedron Lett. 2000, 41, 8041 – 8044; k) T.
Shibata, K. Takasaku, Y. Takesue, N. Hirata, K. Takagi, Synlett
2002, 1681 – 1682.
[5] a) A. Fürstner, P. W. Davies, Angew. Chem. 2007, 119, 3478 –
3519; Angew. Chem. Int. Ed. 2007, 46, 3410 – 3449; b) D. J.
Gorin, F. D. Toste, Nature 2007, 446, 395 – 403; c) E. JimØnez-
Nfflæez, A. M. Echavarren, Chem. Commun. 2007, 333 – 346;
d) For gold-catalyzed formal Diels–Alder reaction involving
furans, see: A. S. K. Hashmi, M. Rudolph, J. P. Weyrauch, M.
Wölfle, W. Frey, J. W. Bats, Angew. Chem. 2005, 117, 2858 – 2861;
Angew. Chem. Int. Ed. 2005, 44, 2798 – 2801.
Representative procedure (Table 3, entry 2): NEt3 (70 mL, 0.51 mmol)
was added to a solution of 1b (X = NTs) (140 mg, 51 mmol)[20] and CuI
(9.7 mg, 0.51 mmol) in CH2Cl2 (2 mL) to give a cloudy yellow
solution. After stirring the reaction mixture for 16 h, it was
concentrated, and the residue purified by flash chromatography
(hexanes/EtOAc, 85:15) to give 2b as a white solid (133 mg, 95%).
M.p. 110–1128C; 1H NMR (400 MHz, CDCl3): d = 7.68 (d, J = 8.3 Hz,
2H), 7.28 (d, J = 8.3 Hz, 2H), 5.74 (dddd, J = 10.0, 3.5, 2.7, 1.2 Hz,
1H), 5.63 (ddq, J = 10.0, 2.1, < 1 Hz, 1H), 5.52 (m, 1H), 3.98 (ddt, J =
13.2, 2.6, 1.7 Hz, 1H), 3.80 (ddd, J = 8.8, 8.0, < 1 Hz, 1H), 3.69
(dquint, J = 13.2, 1.6 Hz, 1H), 2.94 (m, 1H), 2.63 (dd, J = 11.4, 8.8 Hz,
1H), 2.59 (m, 2H), 2.39 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d = 143.4, 134.8, 133.7, 129.6, 127.5, 126.7, 123.1, 117.1, 52.8, 50.7, 37.8,
26.6, 21.5 ppm; for the full data set, see the Supporting Information.
Copper-catalyzed Diels–Alder/alkylation cascade: A solution of
substrate 21c (X = I, 30 mg, 68 mmol) in THF (1 mL) was added to a
solution of copper mesitylene (15 mg, 82 mmol) in THF (1 mL) at
ꢀ788C. The resulting mixture was warmed to room temperature and
stirred for 16 h to give a cloudy dark brown solution. Water (0.5 mL)
was added and the mixture diluted with Et2O (20 mL). The organic
layer was washed with water (2 ” 10 mL), dried (MgSO4), and
evaporated to dryness, before purifying the residue by flash chroma-
tography (hexanes/EtOAc, 4:1) to give 35 as a clear oil which
solidified upon standing (17 mg, 81%). 1H NMR (400 MHz, CDCl3):
d = 7.70 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 5.84 (dt, J = 9.6,
2.3 Hz, 1H), 5.61 (ddd, J = 9.6, 2.8, 1.9 Hz, 1H), 3.92 (dddt, J = 13.8,
3.6, 2.2, 1.8 Hz, 1H), 3.85 (dd, J = 9.0, 8.2 Hz, 1H), 3.62 (ddm, J =
13.8, 1.8 Hz, 1H), 3.03 (dddt, 1H, J = 11.2, 8.0, 3.0, 1.6 Hz), 2.69 (m,
[6] The loss of the trimethylsilyl (TMS) group after work-up is
ascribed to a cleavage mechanism assisted by the soft transition-
metal cation as previously described for Ag+, see A. Fürstner, K.
Radkowski, Chem. Commun. 2002, 2182 – 2183. Increased steric
8848 www.angewandte.org
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Angewandte
Chemie
bulk severely hampers such a process, which might explain why
the Bu3Sn group in 9a is retained.
raises the energy of the highest occupied molecular orbital
(HOMO) to some extent. Therefore, [4+2] cycloadditions with
“normal” as well as “inverse” electron demand should both
benefit from formation of an acetylide.
[7] a) M. MØndez, M. P. Muæoz, A. M. Echavarren, J. Am. Chem.
Soc. 2000, 122, 11549 – 11550; b) L. Charruault, V. Michelet, R.
Taras, S. Gladiali, J.-P. GenÞt, Chem. Commun. 2004, 850 – 851;
c) L. Zhang, S. A. Kozmin, J. Am. Chem. Soc. 2005, 127, 6962 –
6963.
[8] a) A. Fürstner, H. Szillat, B. Gabor, R. Mynott, J. Am. Chem.
Soc. 1998, 120, 8305 – 8314; b) A. Fürstner, F. Stelzer, H. Szillat,
J. Am. Chem. Soc. 2001, 123, 11863 – 11869; c) A. Fürstner, P. W.
Davies, T. Gress, J. Am. Chem. Soc. 2005, 127, 8244 – 8245; d) V.
Mamane, T. Gress, H. Krause, A. Fürstner, J. Am. Chem. Soc.
2004, 126, 8654 – 8655.
[14] B. M. Trost, R. E. Brown, F. D. Toste, J. Am. Chem. Soc. 2000,
122, 5877 – 5878.
[15] T. Tsuda, T. Yazawa, K. Watanabe, T. Fujii, T. Saegusa, J. Org.
Chem. 1981, 46, 192 – 194.
[16] B. H. Lipshutz, S. Sengupta, Org. React. 1992, 41, 135 – 631.
[17] As indicated for 35, the NMR spectra of all the cis-fused
compounds show an unusually large 5J coupling between the
bridgehead protons.
[18] X-ray crystal structure analysis of 35: C18H21NO2S, Mr =
[9] C. Nieto-Oberhuber, S. López, A. M. Echavarren, J. Am. Chem.
Soc. 2005, 127, 6178 – 6179.
315.42 gmolꢀ1, colorless plate, 0.15 ” 0.05 ” 0.05 mm, triclinic,
¯
space group P1, a = 8.9680(8), b = 14.2768(12), c =
[10] a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. 2002, 114, 2708 – 2711; Angew. Chem. Int. Ed.
2002, 41, 2596 – 2599; b) C. W. Tornøe, C. Christensen, M.
Meldal, J. Org. Chem. 2002, 67, 3057 – 3064; c) F. Himo, T.
Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman, K. B.
Sharpless, V. V. Fokin, J. Am. Chem. Soc. 2005, 127, 210 – 216;
d) C. Nolte, P. Mayer, B. F. Straub, Angew. Chem. 2007, 119,
2147 – 2149; Angew. Chem. Int. Ed. 2007, 46, 2101 – 2103; e) for a
review, see V. D. Bock, H. Hiemstra, J. H. van Maarseveen, Eur.
J. Org. Chem. 2006, 51 – 68.
14.4565(10) Š, a = 111.586(4), b = 98.551(4), g = 105.550(3)8,
V= 1593.7(2) Š3, T= 100 K, Z = 4, 1calcd = 1.315 gcm3, l =
0.71073 Š, m(MoKa) = 0.210 mmꢀ1, Gaussian absorption correc-
tion (Tmin = 0.96, Tmax = 0.99), Nonius KappaCCD diffractome-
ter, 2.97 < q < 27.50, 17724 measured reflections, 7230 inde-
pendent reflections, 4175 reflections with I > 2s(I), structure
solved by direct methods and refined by full-matrixleast-squares
against F2 to R1 = 0.075 [I > 2s(I)], wR2 = 0.223, 397 parameters,
H atoms riding, S = 1.047, min./max. residual electron density
+ 0.5/ꢀ0.5 eŠꢀ3. CCDC-652457 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[11] G. D. Allred, L. S. Liebeskind, J. Am. Chem. Soc. 1996, 118,
2748 – 2749.
[12] a) L. F. Tietze, G. Kettschau, Top. Curr. Chem. 1997, 189, 1 – 120;
b) D. L. Boger, S. M. Weinreb, Hetero Diels–Alder Methodology
in Organic Synthesis, Academic Press, San Diego, 1987.
[13] Calculations for 1 (X = NMs; Spartan ꢀ02, DFT-B3LYP; Møller
Plesset MP2/6-31G** for frontier orbital energy calculations)
indicate that formation of a copper acetylide significantly lowers
the lowest unoccupied molecular orbital (LUMO), but also
[19] For related products formed by an entirely different route, see D.
Tanaka, Y. Sato, M. Mori, J. Am. Chem. Soc. 2007, 129, 7730 –
7731.
[20] Y. Ni, J. Montgomery, J. Am. Chem. Soc. 2004, 126, 11162 –
11163.
Angew. Chem. Int. Ed. 2007, 46, 8845 –8849
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8849
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